The present invention relates to transdermal drug delivery systems. More particularly, the present invention relates to transdermal drug delivery systems for delivering pharmaceutically effective amounts of ACE inhibitors, preferably enalaprilat, and to methods of making and using the same.
The use of a transdermal drug delivery system, for example a pressure-sensitive adhesive containing a medicament, namely, a drug, as a means for administering therapeutically effective amounts of the medicament is well known. Such known delivery systems involve incorporation of a medicament into a carrier such as a polymeric and/or a pressure-sensitive adhesive formulation or other forms of carriers. The pressure-sensitive adhesive must adhere effectively to the skin and permit migration of the medicament from the carrier through the skin and into the bloodstream of the patient. The delivery system is an effective means for introducing drugs into the blood stream by applying a patch to skin. The major penetration pathway of drug molecules through the stratum corneum of intact human skin is by diffusion of the drug through the lipid envelopes of the skin cells.
The use of transdermal drug delivery systems for some drug classes is disclosed in the art. For example, steroids such as estradiol and norethindrone are especially well known for use in transdermal drug delivery systems, in particular, as hormone replacement therapy. See U.S. Pat. Nos. 6,221,383 and 5,474,783, both of which are assigned to Noven Pharmaceuticals, Inc. of Miami, Fla. Lipophilic prodrugs of other pharmaceutically active agents such as the anti-asthmatic cromolyn (Bodor et al, International Journal of Pharmaceutics 7 (1980) 63-75), anti-neoplastic fluorouracil (Beall, Dissertation Abstracts International 53 (1992) 859-B), anti-psoriatic methotrexate (Fort, Dissertation Abstracts International 50 (1 990) 5005-B), and anti-herpes drug idoxuridine (Narurkar et al, Pharmaceutical Research 5 (1988) S-98) have been studied with respect to transdermal drug delivery systems.
One problem typically encountered in the development of transdermal drug delivery systems is the polarity of parent drugs, such as those mentioned above, which can significantly attenuate the rate of drug delivery (commonly called xe2x80x9cfluxxe2x80x9d or xe2x80x9cpermeation ratexe2x80x9d) from a transdermal drug delivery system. One promising solution to this problem, as implicated in the above-referenced art, focuses on the administration of lipophilic prodrugs that exhibit somewhat enhanced penetration of skin. Conversion of a lipophilic simple ester prodrug, for example, back into the polar and hydrophilic parent carboxyl-containing drug typically occurs via enzymatic reactions in the skin, Accordingly, prodrugs which are too small (e.g., of low molecular weight) may pass quickly through the skin and would thus not persist long enough in the skin to be transformed back into the parent drugs. Despite these complications, circumstances wherein therapeutic levels of a drug can be successfully attained via transdermal administration offer a number of desirable advantages of this route over other routes of drug administration. Transdermal administration of a drug is often convenient and comfortable for a patient. Control of flux with a single continuous application allows delivery of a sufficiently therapeutic yet non-toxic level of a drug. In contrast, oral administration of many drugs is sometimes unfeasible in view of significant drug decomposition in the gastrointestinal tract, lack of absorption from the gastrointestinal tract, and gastrointestinal upset or damage. Transdermal delivery of a drug also by-passes the first phase of hepatic metabolism, thereby lowering the overall minimum required dosage of the drug to achieve therapeutic levels.
In view of the limited number of drugs administered transdermally, there are applications where it is desirable to administer other drugs percutaneously instead of, for example, orally or intravenously. One class of drugs hitherto believed to be unsuitable for transdermal delivery is the group of angiotensin-converting enzyme (xe2x80x9cACExe2x80x9d) inhibitors that have become the first-line therapy in treating hypertensive patients. Most ACE inhibitors are bi-peptides that are too hydrophilic to penetrate the lipid layers of skin and are accordingly administered orally, intravenously, or both. The well-known ACE inhibitor enalaprilat is an effective drug for use in the treatment of hypertension and heart failure, and would thus be advantageously administered percutaneously to benefit a patient for the reasons discussed above. See Jackson et al in, xe2x80x9cGoodman and Gilman""s, The Pharmacological Basis of Therapeutics, Ninth Editionxe2x80x9d, pp. 733-758, (J. G. Hardman, L. E. Limbird, P. D. Molinoff, R. W. Ruddon, A. G. Gilman, eds.), McGraw Hill, New York (1996) and Oates in, xe2x80x9cGoodman and Gilman""s, The Pharmacological Basis of Therapeutics, Ninth Editionxe2x80x9d, pp. 780-808, (J. G. Hardman, L. E. Limbird, P. D. Molinoff, R. W. Ruddon, A. G. Gilman, eds.), McGraw Hill, New York (1996). However, enaliprilat is a polar compound because it bears two carboxylic acid moieties in its structure, and therefore exhibits very low flux through skin. Likewise, the orally administered form of enalaprilatxe2x80x94enalapril maleatexe2x80x94is also too polar for efficacious transdermal drug delivery. Despite this drawback, it is believed that the advantageous size (i.e., molecular weight) and attainable therapeutic dosage of enalaprilat present it as an attractive candidate for use in transdermal drug delivery systems. For the foregoing reasons, other ACE inhibitors that share these structural and chemical features with enalapril would also be useful in transdermal drug delivery systems. Thus, it would be desirable to administer to a patient a dermal composition of enalaprilat or enalapril or other pharmaceutically active form of ACE inhibitors in a form suitable for use in transdermal drug delivery systems.
One object of the present invention is to provide a dermal composition that is able to deliver a therapeutically effective amount of a pharmaceutically active form (xe2x80x9cthe drugxe2x80x9d) of an ACE inhibitor selected from the group consisting of enalapril, benazepril, lisinopril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril. Another object of the present invention is to provide a dermal composition of a prodrug of the drug. Yet another object is to provide a transdermal drug delivery system that has a substantially improved flux of the prodrug of the drug compared to that of a system of equal size that employs a more polar derivative of the drug.
In accomplishing the foregoing and other objects, there has been provided according to one aspect of the present invention a dermal composition comprising the prodrug enalapril ethyl ester (shown below) in an amount corresponding to a therapeutically effective amount of the pharmaceutically active drug enalaprilat (also shown below) or enalapril in admixture with a carrier. Other prodrugs contemplated for the dermal composition of the present invention include lipophilic prodrugs of pharmaceutically active forms of ACE inhibitors selected from benazepril, lisinopril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril. In one preferred embodiment, the carrier is a polymer that comprises a pressure-sensitive adhesive. 
According to a second aspect of the present invention, there is provided a method of making a dermal composition described above that comprises converting the drug into a more lipophilic derivative (xe2x80x9cprodrugxe2x80x9d) and forming a mixture of the so-formed prodrug and a carrier. Preferably, the carrier is a polymer and the method further comprises the steps of forming the mixture into a polymer matrix and drying the polymer matrix to remove volatile solvents to form the dermal composition.
According to a third aspect of the invention, there is provided a method of substantially increasing the flux of the drug through the skin of a human or an animal comprising the steps of applying to the skin of an animal or human being, the dermal composition described above, and maintaining the dermal composition in contact with the skin.
According to a fourth aspect of the invention, there is provided a method of treating a human or an animal in need of an angiotensin-converting enzyme (xe2x80x9cACExe2x80x9d) inhibitor with a therapeutically effective amount of the drug, that comprises the steps of applying to the skin of the said animal or human being, the dermal composition described above; and maintaining the dermal composition in contact with the skin for a predetermined length of time sufficient to administer a therapeutically effective amount of the drug. This aspect of the present invention thus provides for the treatment of conditions such as hypertension, heart failure, myocardial infarction, and nephropathy.